Drugs, Environment, Brain, and Behavior

The effects of psychoactive drugs are not just a function of their pharmacological actions, but are due to complex interactions among pharmacological, psychological, and environmental factors. We discuss here how drug-environment interactions determine the likelihood that addictive drugs produce a persistent form of neurobehavioral plasticity (sensitization) thought to be involved in the pathophysiology of addiction and relapse. KEYWORDS—sensitization; neuroplasticity; addiction; relapse; genes In humans, the behavioral and subjective effects of drugs vary enormously, even within the same individual, because drug effects are due to complex interactions among pharmacological, psychological, and environmental factors—for instance, whether a drug is taken in a drug-associated environment (e.g., a ‘‘crack house’’), whether drug paraphernalia (e.g., syringes, pipes) are present, and what expectation the individual has about the drug. That many Vietnam combat troops who became dependent on heroin while in Vietnam discontinued use upon their return to the United States illustrates the influence of environmental factors on drug use. Early laboratory studies on drug-environment interactions typically used operant conditioning procedures to study the effects of different schedules of reinforcement (i.e., variations in when and how often behavior is reinforced). For example, in pigeons, the anesthetic pentobarbital either increases or decreases bar pressing to obtain food, depending on the schedule of reinforcement in place at the time the drug is administered. An especially compelling demonstration of how even a simple manipulation of environmental context can influence drug effects is the observation that the lethal dose of amphetamine in mice varies up to 10-fold depending on whether the drug is given in a large or small test cage, or to singlyor group-housed animals (see Kelleher & Morse, 1968, for reviews of the early literature). Nonetheless, there has been very little work on how drug-environment interactions influence the behavioral and neurobiological effects of drugs of abuse, and there has been even less consideration of drug-environment interactions when drugs are administered repeatedly, as would be the case in developing addicts. In this article, we focus on how environmental conditions in which drugs are experienced modulate long-lasting changes in the brain (i.e., neuroplasticity) that are caused by drug exposure—changes that are thought to be important in the transition to addiction and in relapse. DRUGS CHANGE THE BRAIN When a drug is taken repeatedly, some of its effects may decrease, or show tolerance, while other effects increase, or show sensitization. Historically, tolerance, and its role in the development of physical dependence, has been a central focus of research on addiction. However, increasing evidence suggests that long-lasting neurobiological changes related to sensitization play a critical role in addiction (Robinson & Berridge, 2003). This is in part because the behavioral and psychological drug effects that undergo sensitization include effects on motor activation (psychomotor sensitization), incentive motivation (incentive sensitization), and the ability of drugs to sustain or reinforce drug-taking behavior (sensitization of drug reward). All of these behaviors and psychological processes are mediated in part by a neural circuit that involves the neurotransmitter dopamine and connects to many forebrain structures, in particular, the dorsal striatum, nucleus accumbens, prefrontal cortex, and related neural circuitry. Indeed, it is generally recognized that these dopamine circuits are crucial for sensorimotor function and for the reward value of natural stimuli, such as food, drink, and sex, as well as drugs. It is not surprising, therefore, that sensitization-related neuroplastic changes have been found in many components of this circuitry, and it is hypothesized that these brain changes may render individuals hypersensitive to the incentive motivational effects of drugs and thereby contribute to the transition to addiction (Robinson & Berridge, 2003). Therefore, identifying factors that influence susceptibility to sensitization may help researchers understand some of the variability in susceptibility to drug addiction and relapse. ENVIRONMENTAL MODULATION OF BEHAVIORAL